ANTIBACTERIAL OPTIMIZATION OF 4-AMINOTHIAZOLYL ANALOGUES OF THE NATURAL PRODUCT GE2270 A: IDENTIFICATION OF THE CYCLOALKYLCARBOXYLIC ACIDS.

MedLine Citation:

PMID:
21999529
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over that of previous analogs and GE2270 A. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkyl-carboxylic acid sidechains, and culminated in the selection of development candidates amide 48 and urethane 58.